tbuckley/cabot-search huggingface dataset:
NIMG-36. IMAGE LOCALIZATION OF CLINICAL SAMPLES IN BRAIN CANCER: A PROSPECTIVE PROTOCOL
Authors: Jazlynn Langworthy, Lee Curtin, Albana Spahiu, Nora Schafer, Bernard Bendok, Leslie Baxter, Leland Hu, Richard Zimmerman, Kristin Swanson
Journal: Neuro-Oncology (2023)

Abstract It has been widely acknowledged that limited access to the human brain, along with the importance of its structures, presents significant challenges in obtaining brain tumor tissue. This poses difficulties for clinical decision-making, as healthcare professionals often have to rely solely on imaging to address complex problems. There is currently no definitive method to make these decisions other than relying on informed yet subjective human judgment. That said, imaging abnormalities are a result of a presence of particular tumor-related biology. Because of this, and the heterogeneity frequently observed in brain tumors, we have developed an image-localized biopsy protocol that has been employed for research purposes at Mayo Clinic Arizona for over five years. This multidisciplinary approach involves the collaborative efforts from neurosurgeons, neuro-oncologists, scrub-techs, nurses, radiologists, as well as multiple research labs, all working within a well-established pipeline. The implementation of this protocol has allowed us to obtain image-localized biopsies during surgical procedures, enabling the correlation of local imaging findings with corresponding tissue features through the utilization of machine learning models. The primary objective of this endeavor is to enhance our understanding of the underlying biological mechanisms of brain tumors based on patients' imaging data. This protocol has been successful for our research purposes, and with minor adjustments, it can be readily adopted by any hospital in order to collect more data about these incredibly heterogeneous diseases. While the use of neuronavigation during surgery has become commonplace in many medical institutions, localization of tissue samples is not. Utilizing pre-existing infrastructure in the operating room is a small burden with big potential positive outcomes. Sample locations can be useful to clinicians during tumor board discussions, to better assess disease heterogeneity. These minor refinements in the surgical workflow have the capacity to provide clinicians with additional clinically-relevant data without disrupting patient care.
RADT-32. USING NEUROANATOMICAL SUBSITE TO PREDICT PATTERNS OF GLIOBLASTOMA INFILTRATION: POTENTIAL FOR INDIVIDUALISING RADIATION THERAPY TARGET VOLUME DELINEATION OF THE PARIETAL AND POSTERIOR FRONTAL REGIONS
Authors: Michael Back, Patrick Horsley, Jackie Yim, James Drummond
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Radiation therapy(IMRT) protocols for glioblastoma utilize isotropic margin expansion around neurosurgical cavities/residual contrast enhancing(T1gd) disease. However pathways of infiltration may be associated with white matter tract(WMT) involvement varying between neuroanatomical subsites. Posterior frontoparietal tumours involving posterior cingulate region (PostCing) may have extensive infiltration centrally. This study aims to quantify the PostCing infiltration pathway/relapse sites. METHODS Consecutive patients managed for GBMwt with IMRT between 1/2016-6/2022 were classified into 15 neuroanatomical subsites. Tumour segmentation on T1-gadolinium-enhanced(T1gd) and T2-weighted(T2) sequences was performed at diagnosis/relapse. Subsites of Frontal Lobe (Posterior) and Parietal Lobe (Superior/Posterior/Lateral) were identified. On both sequences involvement of adjacent/distant regions (cingulate gyrus, cingulum, splenium, ventricular trigone, parahippocampal-hippocampal gyrus) were identified; as were major WMT: cingulum-parahippocampal formation(CING-PHG), and arcuate fasciculus–inferior longitudinal fasciculus(AF-ILF). Survival was analysed in relation to pattern of infiltration and site of relapse. RESULTS Of 348 patients with glioblastoma, fifty-five(16%) involved PostCing region. Pre-IMRT features included near-total resection in 25%; impaired ECOG 2-3 in 47%; and 58% MGMT-methylated. Parietal lobe tumours(67%) were predominantly posterior(42%) with only 7% lateral parietal. WMT involvement was evident in 94% with T1gd(62%), and T2 alone(33%) abnormality. Infiltration to distal sites of cingulum/splenium/PHG was frequent and predictable; correlating to cingulum pathway involvement in 70% of patients. Median RFS and OS was 13.2 months(95%CI: 11.8-14.8) and 16.6 months(95%CI:14.8-18.5) respectively. Distant relapse was evident in 53% of relapses. In the forty-four Stupp60Gy patients, distant relapse occurred later and was associated with improved overall survival(p = 0.02). No difference in RFS(p = 0.82) or OS(p = 0.31) was noted if tract involvement was either T1gd or T2 alone abnormality. CONCLUSION For glioblastoma in posterior cingulate region, the infiltration and relapse pathways followed white matter tracts in a predictable distribution with high rate of distant disease at diagnosis and relapse. IMRT potentially may be individualised for neuroanatomical subsite and non-isotropic target volume expansion.
CTIM-29. FINAL EFFICACY AND CORRELATIVE ANALYSES OF 2-THE-TOP: A PILOT STUDY OF TTFIELDS (OPTUNE) PLUS PEMBROLIZUMAB PLUS MAINTENANCE TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM)
Authors: David Tran, Dongjiang Chen, Son Le, Ashley Ghiaseddin
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION TTFields induce anti-tumor immunity via the STING and AIM2 inflammasomes. Thus, TTFields-treated GBM cells may provide a complete in situ vaccination platform and synergize with immune checkpoint inhibitors to prolong survival in GBM patients. METHODS We enrolled 26 ndGBM patients in a pilot study combining TTFields, pembrolizumab and maintenance temozolomide (TMZ). To distinguish immune effects of TTFields from pembrolizumab, TTFields starts at cycle 1 of TMZ while pembrolizumab (200mg Q3Wks) at cycle 2. The primary endpoint is PFS versus a case-matched cohort of 56 patients from the EF-14 study. Secondary endpoints include OS, toxicity, and mechanism of response by multiomics of PBMCs and tumors. RESULTS The median age was 60.5 years. Fourteen (54%) had biopsy only or partial resection. Nineteen (73%) had unmethylated MGMT and 3 (11.5%) had an IDH mutation. Median PFS was 12.0 months versus 5.8 months in controls (HR = 0.377; 95CI: 0.217-0.653; P = 0.0026). Median OS was 24.8 months versus 14.6 months in controls (HR = 0.522; 95CI: 0.301-0.905; P = 0.047). Importantly, residual tumor size positively correlated with the objective response and survival. Six of 15 (40%) patients with measurable disease achieved partial to complete response. The most common SAEs were thromboses, seizures, and metabolic disturbances in 4 (15%), 3 (11.5%), and 2 (7.7%) patients, respectively. Molecular analyses confirmed robust T cell activation by TTFields via T1IFN-dependent plasmacytoid dendritic cells (Spearman coefficient = -0.8; P = 0.014). Successful clonal replacement of the most expanded T cell clones after pembrolizumab strongly predicted objective responses to the triple combination in a Cox HR fit model (concordance rate = 0.876; P = 0.031). CONCLUSIONS The triple combination was well tolerated and demonstrated promising efficacy in ndGBM. Bulky residual disease was associated with better outcomes, consistent with the in-situ immunizing properties of TTFields, which synergize with pembrolizumab. Additional molecular analysis will be updated
NIMG-35. RADIO-PATHOMIC MAPS OF TUMOR PROBABILITY IDENTIFY GLIOBLASTOMA INVASION BEYOND 5-ALA GUIDED RESECTION MARGINS THAT EVENTUALLY EXHIBIT TUMOR RECURRENCE
Authors: Aleksandra Winiarz, Samuel Bobholz, Allison Lowman, Savannah Duenweg, Margaret Stebbins, Michael Flatley, Biprojit Nath, Fitzgerald Kyereme, Jennifer Connelly, Dylan Coss, Max Krucoff, Anjishnu Banerjee, Peter LaViolette
Journal: Neuro-Oncology (2023)

Abstract Current standard of care for glioblastoma includes surgery followed by chemotherapy and radiation, with extent of resection strongly correlated with survival. There is a need to improve the detection of tumor invasion beyond traditional imaging methods, as the full extent of tumor is known to be underestimated. Fluorescence-guided surgery with 5-Aminolevulinic acid (5-ALA) allows surgeons to visualize tumor cells beyond what is seen within traditional MR imaging margins. In this study, we compared tumor probability maps (TPMs) that detect tumor outside of contrast enhancement (CE) to the 5-ALA-guided resection cavity in glioblastoma patients. 3 pathologically confirmed glioblastoma patients that followed standard of care and underwent 5-ALA surgery were included. Patient 1 was a 56-year-old male with radiographic recurrence at 26 days, patient 2 was a 61-year-old male with radiographic recurrence at 130 days, and patient 3 was a 72-year-old male with cystic recurrence at 84 days, all post 5-ALA surgery. A previously published algorithm, using T1, T1C, FLAIR, and ADC as input and autopsy tissue as ground truth, was used to generate TPMs. Pre-surgical TPMs were qualitatively compared to pre-surgical CE, post-5-ALA surgical resection cavities, and radiographic recurrence seen as CE. In patients 1 and 2, TPMs identified areas suspicious of tumor that was not resected and later exhibited radiographic recurrence. Patient 3 had cystic recurrence only identified on post-resection T1C. In all patients, the extent of 5-ALA resection was greater than CE volume, but smaller than TPM identified tumor. These findings suggest that there was residual tumor that was unidentified via 5-ALA and traditional imaging but was identified by the TPMs. Future studies could utilize these maps in conjunction with 5-ALA to maximize surgical resections and prolong overall survival.
TMIC-15. GENETIC AND SPATIAL HETEROGENEITY OF PEDIATRIC HIGH-GRADE GLIOMAS CONFER UNIQUE INFLAMMATORY MICROENVIRONMENTS
Authors: James Ross, Gonzalo Pinero, Montserrat Puigdelloses-Vallcorba, Nishant Soni, Angelo Angione, Oren Becher, Alexander Tsankov, Dolores Hambardzumyan
Journal: Neuro-Oncology (2023)

Abstract Significant progress has been made molecularly defining pediatric high-grade gliomas (pHGG), including diffuse midline gliomas (DMG), yet little progress has been made with respect to delineating the inflammatory microenvironment. We utilize molecularly defined human samples and immunocompetent genetic mouse models to study how tumor location and genetic driver mutations influence the tumor microenvironment (TME). We report human DMGs have a significant enrichment of Elane+ neutrophils compared to their hemispheric counterparts. We validate this utilizing the RCAS-Tva mouse model, which histologically and genetically recapitulates human pHGGs. Using this model we demonstrate each distinct pHGG/DMG entity confers unique transcriptional identities as made evident by NanoString RNA expression profiles and whole-tumor single-cell RNA sequencing. H3.3WT DMGs and H3.3K27M DMGs cluster together and have high expression of inflammatory genes such as Ptprc, Trem2, Lag3, and Cd274 while H3.3WT and H3.3G34R hemispheric tumors, and H3.1K27M DMGs cluster together with low expression of these genes. Several genes were found to significantly correlate with median survival in human bulk RNA sequencing data including IL13RA2. Flow cytometry and immunohistochemistry demonstrate H3WT DMGs are enriched for monocytes and lymphocytes while H3.3K27M DMGs are enriched for microglia. Genetic perturbations were made to prevent TAM or neutrophil infiltration, including targeting Ccl3, Cxcl1, and Ccl8/12. Only Ccl8/12 knockout resulted in significant extension of survival in H3K27M DMGs, which was met with an increase in CD4+ and CD8+ T-cells and decreased neutrophil infiltration. CD4+ T-cell depletion and anti-PD1 therapy was performed to further study the role of lymphocyte infiltration in DMGs. Lastly, CCR1/CCR5 inhibitors were utilized to abrogate TAM infiltration in DMGs, resulting in decreased microglia infiltration and significant survival extension comparable to radiation therapy. Together, this work provides the foundation for developing or improving immunotherapies designed at specific subgroups of pHGG and DMGs, such as CAR-T-cell, oncolytic viral therapy, and checkpoint blockade.
NIMG-06. BRAINSTEM NON-ENHANCING DIFFUSION-RESTRICTING T2 FLAIR HYPERINTENSITY AFTER EGFR TYROSINE KINASE INHIBITORS: AN EARLY SIGN OF LEPTOMENINGEAL DISEASE?
Authors: Jaspreet Kaur, Nhat-Long Pham, Omer Ilyas, Fan Mo, Silin Bao, Carlen Yuen
Journal: Neuro-Oncology (2023)

Abstract Leptomeningeal disease (LMD) is a late complication of non-small cell lung cancer (NSCLC) patients and carries poor prognosis. The discovery of EGFR mutations as actionable drivers launched a new treatment paradigm with EGFR tyrosine kinase inhibitors (TKIs) for NSCLC patients, including those with LMD. LMD is characterized by leptomeningeal enhancement on post-contrast MRI. Adverse effects of EGFR TKIs are well described, but little is known about non-enhancing LMD in this patient population. Previously described only in case studies, this rare and novel imaging abnormality is characterized by non-enhancing band-like diffusion-restricting T2 hyperintensity surrounding the brainstem and is thought to be an early marker of LMD. Positive CSF cytology confirms the diagnosis. The mechanism is unknown, but is thought to be a result of highly cellular tumor invasion and subsequent capillary microinfarctions. Early evidence suggests that NSCLC patients with non-enhancing cerebral hemispheric LMD carry improved overall survival compared to those with contrast-enhancing disease. We present a case of a 75-year-old female with NSCLC brain metastases responsive to 3 EGFR inhibitors and non-enhancing brainstem LMD. Three CSF cytologic examinations were negative for malignant cells. She remains clinically and radiographically stable at 8-month follow-up. This case is significant because it contributes to the small existing body of literature for this atypical radiographic finding. We propose that non-enhancing LMD in NSCLC patients being treated with EGFR TKIs is a potential surrogate marker for response to treatment.
STEM-15. STAT5-OLIG2 TRANSCRIPTIONAL COMPLEX MEDIATES GLIOMA STEM CELL SELF RENEWAL AND INVASION
Authors: Aunay Miller, Costanza Lo Cascio, Mylan Blomquist, James McNamara, Keely Orndorff, Matthew Dufault, Christopher Sereduk, Joseph Loftus, Shwetal Mehta, Nhan Tran
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults, despite current treatment options. One of the major contributing factors to this dismal outcome is a subset of cells called glioma stem cells (GSCs) that are highly tumorigenic, invasive, and resistant to conventional treatments. Thus, studies that focus on the properties of GSC biology are needed to develop novel therapies to improve overall survival. Here we report a novel role of STAT5 in GSC stemness and survival. In GBM tumors, STAT5 has been shown to be active in the infiltrative, residual population of cells remaining post-surgery. Knockdown of STAT5 results in the decrease in GSC stemness and therapeutic resistance. Interestingly, we find that expression of OLIG2, a key cell fate factor important for the tumorigenic potential of GSCs, affects STAT5 activation with a positive correlation between OLIG2 and STAT5 mRNA expression in GBM tumors. Furthermore, we find that in GSCs expressing EGFRvIII, STAT5 interacts with OLIG2 and pharmacological inhibition of STAT5 activation or knockdown of STAT5 expression results in decrease of OLIG2-mediated GSC invasion. Together, these data suggest a novel transcriptional complex, STAT5-OLIG2, in the potential role for GSC survival, maintenance, and invasion.
TMIC-59. IL-2 SECRETING ENGINEERED MYELOID CELLS POTENTIATE CYTOTOXIC EFFECTOR CELL ACTIVATION TO DELAY MALIGNANT PROGRESSION IN A PRECLINICAL MODEL OF GLIOMA
Authors: Alessandro Canella, Matthew Nazzaro, Abigail Haffey, Claire Schmitt, Gregory Behbehani, Prajwal Rajappa
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Gliomas are the most prevalent brain tumor in the adolescent and young adult population (AYA) and one of the leading causes of cancer-related death. In fact, two-thirds of glioma AYA patients are affected by low-grade gliomas (LGGs). Moreover, there are no therapies to prevent glioma LGG malignant progression. Malignant progression is associated with a significant reduction of tumor infiltrating cytotoxic effector immune cells, primarily due to the immunosuppressive tumor microenvironment (TME) mediated by regulatory T lymphocytes, tumor associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). To that end, immunotherapies have had limited efficacy in improving outcomes for primary and secondary HGGs. HYPOTHESIS We hypothesize that engineered myeloid cells that release IL-2 will enhance the trafficking of activated effector T cells and potentiate a pro-inflammatory cascade in the low-grade glioma TME, delaying malignant progression. METHODS Immunocompetent RCAS n/tv-a LGG bearing animals were retro-orbitally treated at day 21 with a single dose of bone-marrow derived myeloid cells, engineered for the release of Interlekin-2 (GEMys-IL2). The inflammatory status of the TME along with the composition and functional status of tumor infiltrating immune cells were investigated in vivo by cytokine array, mass cytometry, and bulk RNA sequencing. RESULTS Our complementary dataset demonstrated that GEMys-IL2 infiltrated the glioma microenvironment and triggered a pro-inflammatory cascade involving the upregulation and release of IL2, IFNy, CXCL9, Tim1, CD26 and other pro-inflammatory cytokines associated with the activation and recruitment of innate and adaptive immune cells within the TME. In addition, we observed a downregulation of immunosuppressive signaling pathways such as IL10, PPAR, LXR/RXR, CTLA4 and PD-1. Also, a single dose of GEMys-IL2 systemically injected in RCAS/t-va immunocompetent LGG bearing mice potentiated pro-inflammatory remodeling of the TME and significantly improved overall survival. CONCLUSIONS These preclinical studies highlight a novel approach in developing next-generation innate immunotherapies.
TMET-15. THE COMBINATIONAL EFFECT OF INHIBITOR FOR A FATTY ACID DESATURASE AND A FATTY ACID TRANSPORTER ON GLIOMA GROWTH
Authors: Tomohiro Yamasaki, Lumin Zhang, Tyrone Dowdy, Adrian Lita, Kazuhiko Kurozumi, Mioara Larion
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND It is not well understood how much exogenous fatty acids uptake and de novo fatty acid synthesis affect the cell proliferation in glioma. In this study, we examined the combinational effect of inhibitor for a fatty acid desaturase (SCD) and a fatty acid transporter (CD36) on glioma growth. METHODS Normal human astrocytes (NHA) were used as glial cells, and U251 transfected with IDH wild-type or IDH mutant gene and patient-derived glioma cells (BT142, TS603, GSC923S) were used as glioma cells. The function of SCD was suppressed by SCD inhibitor and SCD siRNA, and Sulfo-N-succinimidyl oleate (SSO) was used to inhibit the CD36 function. RESULTS We treated U251 cells with palmitic acid (C16:0), stearic acid (C18:0), palmitoleic acid (C16:1) or oleic acid (C18:1) after SCD inhibitors treatment or SCD knockdown, and cell proliferation was rescued only after the treatment with C16:1 and C18:1. NHA was not affected by SCD inhibitor, although CD36 inhibitor suppressed cell proliferation of both U251 and NHA. The combination of SCD inhibitor and CD36 inhibitor under the addition of exogenous fatty acid, oleic acid, suppressed the proliferation of U251 cells more effectively than SCD inhibitor or CD36 inhibitor alone. Discussion: The SCD inhibitory effect on gliomas was attenuated by the presence of exogenous monounsaturated fatty acids, whereas the CD36 inhibitor enhanced the cell-killing effect. On the other hand, it should be noted that CD36 inhibitors affect the proliferation of glial cells.
TMIC-16. THE COLLAGEN RECEPTOR LAIR-1 ALTERS THE GLIOMA MICROENVIRONMENT AND REGULATES TUMOR AGGRESSIVE BEHAVIOR
Authors: Maria Varela, Syed M Faisal, Andrea Comba, Sayer Lelling, Marcus Barissi, Maria Castro, Pedro Lowenstein
Journal: Neuro-Oncology (2023)

Abstract High-grade gliomas (HGG) are the most common malignant primary brain tumors in adults, with a median survival of 15-18 months. HGG are heterogeneous tumors with a complex extracellular matrix. Our previous work demonstrated the importance of the interaction between tumor cells and Collagen I. Employing genetically engineered mouse models (GEMM) of glioma, we identified Collagen 1α1 (Col1A1) as a regulator of tumor malignancy. Downregulation of Col1A1 in glioma cells extended median survival (MS), and reduced migration and proliferation. Nonetheless, the mechanisms underlining these effects remain unknown. LAIR-1 is a collagen receptor originally described as an inhibitory receptor in immune cells. We now describe the expression of LAIR-1 in glioma cells. Molecular ablation of LAIR-1 from glioma cells in GEMM (NPL: NRAS, shP53, shLAIR-1, and NPAL: NRAS, shP53, shATRX, shLAIR-1) significantly improved MS when compared to controls (NP: NRAS, shP53, and NPAL: NRAS, shP53, shATRX). The NPAL tumors had reduced cell proliferation (PCNA+), higher infiltration of astrocytes (GFAP+) and CD8+ T cells. Cells were obtained from these GEMM and cultured in vitro. LAIR-1 downregulation reduced cell proliferation, in both NPAL and NPL cells. To corroborate LAIR-1’s relationship with cell proliferation, control cells (NPA) were incubated with a LAIR-1 blocking antibody resulting in diminished glioma cell proliferation. When these cells were implanted in the brain LAIR-1 was downregulated resulted in increased MS. In vitro cytokines production assessment showed both NPAL and NPL cell had an enhanced production of RANTES(CCL5), G-CSF and IL-6 production, when compared to their controls. Our data suggest that LAIR-1 expression in glioma cells has a role in glioma malignant behavior both due to tumor cell proliferation and because of tumor composition. We hypothesize that blocking the interaction between LAIR-1 and collagen may improve median survival.